Novel process for preparing α-(trichloromethyl)benzyl alcohols from benzaldehydes

ABSTRACT

This invention relates to a novel and improved process for preparing α-(trichloromethyl) benzyl alcohols, particularly, trichloromethyl-3-nitrobenzyl alcohol a key intermediate useful in the preparation of clorsulon (4-amino-6-(trichloroethenyl)-1,3-benzene-disulfonamide) via a base-catalyzed condensation reaction of benzaldehydes and chloroform.

BACKGROUND OF THE INVENTION

This invention relates to a novel and improved one-step process forpreparing α-(trichloromethyl)carbinols via a base-catalyzed condensationreaction of benzaldehydes and chloroform. One of the compound preparedvia this process, Trichloromethyl-3-nitrobenzyl alcohol is a keyintermediate useful in the preparation of a class of anthelminticdisulfonamide compounds, in particular, the process for preparing4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide also referred toas clorsulon is disclosed in U.S. Pat. No. 4,500,736. The anthelminticcompounds referred to herein are disclosed in U.S. Pat. No. 4,064,239and are particularly useful against liver fluke in sheep and cattle.

DESCRIPTION OF THE PRIOR ART

The condensation of chloroform with benzaldehydes under basic conditionsis a standard method for the preparation of α-(trichloromethyl)benzylalcohols, which serve as intermediates in a variety of syntheticapplications. With highly reactive aldehydes, such asnitrobenzaldehydes, the competing Cannizzaro reaction is often a seriousproblem resulting in low yields or exclusively Cannizzaro products.

Several articles have described the condensation of substitutedbenzaldehyde derivatives with chloroform in the presence of variousbases to produce the corresponding α-(trichloromethyl)benzyl alcohols.In the case of nitrosubstituted benzaldehydes, only Cannizzaro reactionproducts are obtained when powdered potassium hydroxide is used as thebase without solvent. Phase transfer conditions produce a mixture ofnitrobenzoic acid, nitrobenzyl alcohol, and trichloromethylnitrobenzylalcohol. Potassium t-butoxide in liquid ammonia at -75° C. has beenreported to effect the desired condensation to formtrichloromethyl-3-nitrobenzyl alcohol in 72% yield (Ya. G. Bal'on, V. E.Paranyuk, and M. D. Shul'man, Zh. Obsch. Khim., 44, 2633 (1974)). Underthe same conditions potassium hydroxide or calcium oxide in dimethylsulfoxide gives 5-10% lower yields. The generation of trichloromethideanion in solution from the decomposition of trichloroacetic acid indimethyl sulfoxide has been used to preparetrichloromethyl-4-nitrobenzyl alcohol in 60% yield (P. J. Atkins et al.,J. Chem. Soc., Chem. Comm., 1983, pp. 283-4).

SUMMARY OF THE INVENTION

This invention relates to a novel and improved one step process for thepreparation of α-(trichloromethyl)benzyl alcohols, particularly,trichloromethyl-3-nitrobenzyl alcohol, a key intermediate useful in thepreparation of trichlorovinyl benzenedisulfonamide anthelmintic agents.

Accordingly, it is an object of this invention to provide a novel andimproved one-step process for preparing trichloromethyl-3-nitrobenzylalcohol.

A further object of this invention is to describe the specific reactionconditions and reagents which produce an unexpected yield of the keyintermediate, trichloromethyl-3-nitrobenzyl alcohol.

Another object of this invention is to provide reaction conditions whicheliminate the expected Cannizzaro reaction and provide an intermediatein an unexpected high yield without a decrease in product purity.

These and other objects of the invention will become apparent from thefollowing description.

DESCRIPTION OF THE INVENTION

The α-(trichloromethyl)benzyl alcohol compounds prepared via this noveland improved one step process of this invention are represented by thegeneral formula below: ##STR1## wherein R₁ is H; alkoxy(C₁ -C₆) such asmethoxy, ethoxy, isopropoxy and the like; nitro; alkyl (C₁ -C₆) such asmethyl, isopropyl, hexyl and the like; halogen such as chloro, bromo andthe like; amino; aryl (C₆ -C₉) such as phenyl; and aralkyl such asbenzyl(C₇ -C₁₂) and the like.

The invention concerns a novel and improved one-step base condensationprocess for the preparation of α-(trichloromethyl)carbinols,particularly, trichloromethyl-3-nitrobenzyl alcohol, an intermediateuseful in the preparation of trichlorovinyl benzenedisulfonamideanthelmintic agents. The novel and improved one-step process disclosedherein involves a method for condensation of chloroform with aldehydesusing an alkanol such as methanol, ethanol, isopropanol and the like, abase such as potassium hydroxide, sodium hydroxide, calcium hydroxide,sodium methoxide, potassium t-butoxide and the like in a dipolar-aproticsolvent such as dimethylformamide, N-methylpyrrolidinone,N-ethylpyrrolidinone and the like at sub-zero (approximately -25° C.) to0° C. Using this procedure, trichloromethyl-3-nitrobenzyl alcohol isprepared in 90% isolated yield without Cannizzaro by-products. Thismethod is also used to prepare α-(trichloromethyl) carbinols frombenzaldehyde, 4-anisaldehyde, and the like.

In this invention we describe the preparation oftrichloromethyl-3-nitrobenzyl alcohol in high yield with no detectableCannizzaro product and demonstrate the generality of the method for thecondensation of chloroform with other aldehydes and ketones. Initially,potassium fluoride supported on alumina was the base of choice for thiscondensation since the fluoride base would prevent the Cannizzaro sidereaction. Characterization by infrared and Raman spectroscopy of thissupported base showed the presence of potassium hexafluoroaluminaterather than potassium fluoride. Aqueous potassium fluoride had reactedwith alumina to produce potassium hexafluoroaluminate and hydroxide.This observation prompted the use of potassium hydroxide supported onSuper-Cel as the base to give TMBA in 93% isolated yield. The methoddescribed herein avoids the preparation and variable activity of thesupported hydroxide base. A mixture of chloroform (2.25 equivalents) and3-nitrobenzaldehyde (one equivalent) in dimethylformamide (DMF) at 0° C.was treated with a methanolic solution of potassium hydroxide (0.7equivalents). After work-up, the desired alcohol TMBA was obtained in98% yield and crystallized from toluene/hexane to give analytically puretrichloromethyl-3-nitrobenzyl alcohol in 90% yield.

The generality of this method for condensation of chloroform withcarbonyl compounds was examined and the results are summarized in TableI below:

                  TABLE I                                                         ______________________________________                                        Yields of Trichloromethyl Carbinols                                           Carbonyl Compound                                                                         Yield.sup.a,b                                                                          Product                                                  ______________________________________                                        3-nitrobenzaldehyde                                                                       90%      ethyl-3-nitrobenzyl alcohol                              benzaldehyde                                                                              99%      trichloromethylbenzyl alcohol                            4-anisaldehyde                                                                            97%      trichloromethyl-4-methoxybenzyl                                               alcohol                                                  ______________________________________                                         .sup.a All products exhibited the expected .sup.1 H and .sup.13 C NMR and     MS characteristics and gave satisfactory elemental analyses.                  .sup.b Isolated yields after distillation or crystallization.            

This method permits the preparation of a variety of α-trichloromethylcarbinols in high yield using the convenient potassium hydroxide base inmethanol/DMF.

The following examples illustrate the novel and improved process of theinvention and should be construed as an illustration rather thanlimitation thereof.

EXAMPLE I Trichloromethyl-3-nitrobenzyl alcohol (TMBA)

To a solution of 3-nitrobenzaldehyde (200 g, 1.32 mol) and chloroform(238 ml, 2.97 mol) in 800 ml of DMF cooled to -9° C. under nitrogen wasadded dropwise a solution of potassium hydroxide (59.8 g, 0.92 mol) in180 ml of methanol over a 2.7 hour period. The deep purple reactionmixture was aged for 2 hours at -8° C. before quenching over 40 minutesinto 1.8 liter of lN HCl and 1.8 liter of toluene cooled to -5° C. Thequench mixture was stirred and cooled for an additional 0.5 hour andthen brought to ambient temperature. The toluene layer was separated andwashed twice with 1.8 liter of water. After treatment with 35 g of DarcoG-60 charcoal for 1 hour and filtration through Super-Cel, the organiclayer was washed with 1.8 liter of aqueous 5% sodium bicarbonatesolution and then 1.8 liter of water. After evaporation to 550 ml thedesired product was crystallized by the addition of 450 ml of hexanes.The resulting slurry was cooled at 0° C. for 2 hours and the solid wascollected by filtration and rinsed with hexanes. After drying, 320 g(90% yield) of TMBA was obtained; m.p. 91- 95° C; ¹ H NMR 3.75 (1H, d,J=1 Hz), 5.25 (1H, d, J=1 Hz), 7.20-8.45 (5H, m).

Anal. Calc'd for C₈ H₆ NO₃ Cl₃ :

C, 35.52; H, 2.24; N, 5.18; Cl, 39.32 .

Found: C, 35.78; H, 2.23; N, 5.34; Cl, 39.38.

EXAMPLE II

When N-methylpyrrolidinone or N-ethylpyrrolidinone; sodium hydroxide,potassium t-butoxide, calcium hydroxide or sodium methoxide; ethanol orisopropanol are substituted for dimethylformamide, potassium hydroxideand methanol, respectively, under the same reaction conditions employedin Example I, there is obtained trichloromethyl-3-nitrobenzyl alcohol.

EXAMPLE III

Following the procedure of Example I and substituting benzaldehyde,4-anisaldehyde and other starting material compounds and substitutingthe reagents of Example II, there is obtained trichloromethylbenzylalcohol, trichloromethyl-4-methoxybenzyl alcohol and the benzaldehydecorresponding to said starting material compound, respectively.

EXAMPLE IV Trichloromethyl-3-nitrobenzyl alcohol (TMBA)

To a solution of 3-nitrobenzaldehyde (80 g, 0.53 mol) and chloroform (95ml, 1.17 mol) in 320 ml of N-methylpyrrolidinone cooled to -10° C. undernitrogen was added dropwise a solution of potassium hydroxide (24 g,0.43 mol) in 80 ml of methanol over a 40 minute period. The deep purplereaction mixture was aged for 4 hours at -5° C. before quenching into640 ml of lN HCl and 500 ml of methylene chloride cooled to 0° C. Thequench mixture was stirred and cooled for an additional 0.5 hour andthen brought to ambient temperature. The methylene chloride layer wasseparated and washed twice with 720 ml of water, 720 ml of 10% sodiumbisulfite, and again with 720 ml of water. After treatment with 9.0 g ofDarco G-60 charcoal for 1 hour and filtration through Super-Cel, theorganic layer was washed with 450 ml of aqueous 5% sodium bicarbonatesolution and then 720 ml of water, with 65 ml of saturated salt solutionadded. The resulting methylene chloride solution contained 140.2 g(98.4% yield) of TMBA.

What is claimed is:
 1. A process for preparing α-(trichloromethyl)benzylalcohols of the formula ##STR2## wherein R₁ is hydrogen, alkoxy (C₁-C₆), nitro, alkyl(C₁ -C₆), halogen, amino, aryl(C₆ -C₉) or aralkyl (C₇-C₁₂) which comprises condensing a benzaldehyde compound with chloroformin the presence of a dipolar-aprotic solvent and a base in an alkanol ata sub-zero to zero degree temperature.
 2. The process of claim 1,wherein said benzaldehyde compound is selected from the group consistingof 3-nitrobenzaldehyde, benzaldehyde and 4-anisaldehyde; saiddipolar-aprotic solvent is selected from the group consisting ofdimethylformamide, N-methylpyrrolidinone and N-ethylpyrrolidinone; saidbase is selected from the group consisting of sodium hydroxide,potassium t-butoxide, calcium hydroxide, sodium methoxide and potassiumhydroxide; and said alkanol is selected from the group consisting ofmethanol, ethanol and isopropanol at temperature ranging from -25° C. to0° C.
 3. The process of claim 2, wherein said compound is3-nitrobenzaldehyde, said solvent is dimethylformamide, said base ispotassium hydroxide and said alkanol is methanol at temperatures rangingfrom -15° to 0° C.
 4. The process of claim 3, wherein said temperatureis -9° C.
 5. The process of claim 2, wherein said compound isbenzaldehyde, said solvent is N-methylpyrrolidinone, said base ispotassium hydroxide and said alkanol methanol at temperature rangingfrom -15° C. to 0° C.
 6. The process of claim 5, wherein the temperatureis -5° C.
 7. The process of claim 2, wherein said compound is3-nitrobenzaldehyde, said solvent is N-methylpyrrolidinone, said base ispotassium hydroxide and said alkanol is methanol at temperatures rangingfrom -15° C. to 0° C.
 8. The process of claim 7, wherein saidtemperature is -5° C.
 9. The process of claim 2, wherein said compoundin anisaldehyde, said solvent is N-ethylpyrrolidinone, said base ispotassium t-butoxide and said alkanol is methanol at temperaturesranging from -15° C. to 0° C.
 10. The process of claim 9, wherein thetemperature is -10° C.
 11. The process of claim 3, wherein said alkanolis ethanol or isopropanol.
 12. The process of claim 11, wherein saidalkanol is isopropanol.